The present specification provides novel compositions of matter, novel methods of their preparation, and novel intermediates therefor. In particular, the present invention relates to 2,3-didehydro-5-oxopyrrolizidinones and indolizidinones which are useful as lipidaltering and anti-atherosclerotic agents.
Atherosclerosis in mammals is a disease characterized by the deposition of atherosclerotic plaque on arterial walls. While atherosclerosis exhibits many varied forms and consequences, typical consequences of atherosclerotic diseases include angina pectoris, myocardial infarction, stroke, and transient cerebral ischemic attacks. Other forms of atherosclerotic diseases include certain peripheral vascular diseases and other ischemias (e.g., bowel and renal).
Medical science now recognizes that certain forms of atherosclerosis may be preventable or reversible. Agents capable of preventing or reversing atherosclerosis are characterized as exhibiting antiatherosclerotic activity. Since serum lipids have a recognized association with atherogenesis, an important class of antiatherosclerotic agents are those with serum lipid-modifying effects. Serum lipids implicated in atherogenesis include serum cholesterol, serum triglycerides, and serum lipoproteins.
With respect to serum lipoproteins, at least three different classes of these substances have been characterized: high density lipoproteins (HDL's), low density lipoproteins (LDL's), and very low density lipoproteins (VLDL's). HDL's are often referred to as alphalipoproteins, while LDL's and VLDL's are referred to as betalipoproteins. The enhancement to HDL levels (hyperalpha-lipoproteinemic activity) is postulated to have direct antiatherosclerotic effects. See Eaton, R. P., J. Chron. Dis. 31:131-135 (1978). In contrast, agents which reduce serum LDL's and serum VLDL's (hypobetalipoproteinemic agents) are also associated with antiatherogenic effects. See Haust, M. D., "Reaction Patterns of Intimal Mesenchyme to Injury and Repair in Atherosclerosis," Adv. Exp. Med. Biol. 43:35-57 (1974), which postulates that serum LDL is a factor in atherosclerotic lesion formation.
A large number of pyrrolizidine alkaloids and related structures are known in the literature: see the chapters on Pyrrolizidine Alkaloids in the review monographs "The Alkaloids", Vol. 1-12, The Chemical Society, Burlington House, London, 1971-82. These have been isolated from plants and insects. None of these have been reported to have lipid-altering or antiatherosclerotic activity, although they are generally associated with a larger number of toxic and pharmacologic effects. See, C. C. J. Culvenor, D. T. Downing and J. A. Edgar, "Pyrrolizidine Alkaloids as Alkylating and Antimitotic Agents", Ann. N.Y. Acad. Sci., 1969, 163, 837-847; E. K. McLean, "The Toxic Actions of Pyrrolizidine (Senecio) Alkaloids", Pharmacol. Rev., 1970, 22, 429-483; and more recently, the brief review by R. J. Huxtable in Gen. Pharmacol., 10:159 (1979). The biology of pyrrolizidines is also discussed in Culvenor, et al., Chem.-Biol. Interactions, 12:299-324 (1976).
Numerous fused ring systems containing a nitrogen atom are known, e.g., 2-5 membered ring systems (pyrrolizidines), 6 member-5 member ring systems (indolizidine type) and 2-6 membered ring systems (quinolizidine type). See, "The Alkaloids," supra. Certain pyrroletype fused ring systems which contain an enamide function are known and are naturally occurring, Id.
2. Prior Art
Sumoto, et al., J. Heterocyclic Chem. 18:413 (1981) discloses a delta-1,8-dehydropyrrolizidine compound. No use is disclosed for this compound. Cheng, et al., J. Amer. Chem. Soc. 103:2090 (1981) discloses certain fused 5-6 membered and 6--6 membered ring systems which are prepared by a Diels-Alder type reaction. By virtue of their method of synthesis the compounds disclosed therein all have a six-membered olefin ring. No uses are disclosed for these compounds. LaLonde, et al., in J. Org. Chem. 45:3664-3671 (1980) inferred the presence of certain methyl-indolizidones as intermediates for the preparation of certain nuphar indolizidine alkaloids. Finally, Buchs, et al., J. Org. Chem. 47:719 (1982) discloses (E)-5-hydroxypyrrolizidin-3-one, as well as the 5-methoxy and 5-ethoxy derivatives thereof, as intermediates.